Background: We present two brothers with very distinct phenotype, possibly constituting a novel clinical and genetic entity. The common phenotype included red hair, obesity, myopathy, severe IGHD and, growth without growth hormone.
Case presentation: At the age of 28 months the older brother had a height of 68 cm (−9 SD), his bone age was 6 months. The younger brother had a height of 62 cm at the age of 20 months (−5 SD), bone age 10 months. Two tests of pituitary GH reserve showed severe growth hormone deficiency (GHD) in both patients (<0.3 ng/ml). All other pituitary hormones were within normal levels. Rapid growth in the first two years got them on the 30th and 40th percentile on the growth curve. IGF-I and IGFBP3 were not initially available, but under treatment were normal. Leptin measurement was not available. Unsteady gait, falling increased muscle enzymes lead to a diagnosis of myopathy. Two muscle biopsies were inconclusive (Macedonia and Germany). Remarkably, after GH treatment was interrupted growth continued normally and they both reached normal adult target height. Retesting the GH pituitary reserve showed low GH levels <0.3 ng/ml. Extensive genetic investigation included sequencing of the GH1, POMC, MC4R, SMN1, dystrophin and dynactin genes, as well as the complete mitochondrial genome. No gene alterations were detected. The karyotype of the patients is normal 46, XY. Whole exome sequencing (WES) identified a compound heterozygous mutation in the RNPC3 gene, where each parent is heterozygous for one of the variants (RNPC3:NM_017619:exon6:c.613C>T: p.R205X, and RNPC3:NM_017619:exon13:c.1420C> A:p.P474T.
Conclusions: Mutations of the RNPC3 gene encoding 65K protein that is a part of the U12-type spliceosome were identified. At present it is not clear how the mutations cause the IGHD and the myopathy in the patients. Additional functional studies will follow.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology